bims-reprim Biomed News
on Reproductive immunology
Issue of 2020‒09‒20
five papers selected by
Iva Filipovic
Karolinska Institutet


  1. Nat Med. 2020 Sep 14.
    Wang W, Vilella F, Alama P, Moreno I, Mignardi M, Isakova A, Pan W, Simon C, Quake SR.
      In a human menstrual cycle the endometrium undergoes remodeling, shedding and regeneration, all of which are driven by substantial gene expression changes in the underlying cellular hierarchy. Despite its importance in human fertility and regenerative biology, our understanding of this unique type of tissue homeostasis remains rudimentary. We characterized the transcriptomic transformation of human endometrium at single-cell resolution across the menstrual cycle, resolving cellular heterogeneity in multiple dimensions. We profiled the behavior of seven endometrial cell types, including a previously uncharacterized ciliated cell type, during four major phases of endometrial transformation, and found characteristic signatures for each cell type and phase. We discovered that the human window of implantation opens with an abrupt and discontinuous transcriptomic activation in the epithelia, accompanied with a widespread decidualization feature in the stromal fibroblasts. Our study provides a high-resolution molecular and cellular characterization of human endometrial transformation across the menstrual cycle, providing insights into this essential physiological process.
    DOI:  https://doi.org/10.1038/s41591-020-1040-z
  2. Hum Reprod. 2020 Sep 17. pii: deaa234. [Epub ahead of print]
    Windsperger K, Vondra S, Lackner AI, Kunihs V, Haslinger P, Meinhardt G, Dietrich B, Dekan S, Fiala C, Knöfler M, Saleh L, Pollheimer J.
      STUDY QUESTION: Do high endothelial venules (HEVs) appear in the uterus of healthy and pathological pregnancies?SUMMARY ANSWER: Our study reveals that HEVs are present in the non-pregnant endometrium and decidua parietalis (decP) but decline upon placentation in decidua basalis (decB) and are less abundant in decidual tissues from idiopathic, recurrent pregnancy losses (RPLs).
    WHAT IS KNOWN ALREADY: RPL is associated with a compromised decidual vascular phenotype.
    STUDY DESIGN, SIZE, DURATION: Endometrial (n = 29) and first trimester decidual (n = 86, 6-12th week of gestation) tissue samples obtained from endometrial biopsies or elective pregnancy terminations were used to determine the number of HEVs and T cells. In addition, quantification of HEVs and immune cells was performed in a cohort of decidual tissues from RPL (n = 25).
    PARTICIPANTS/MATERIALS, SETTING, METHODS: Position and frequency of HEVs were determined in non-pregnant endometrial as well as decidual tissue sections using immunofluorescence (IF) staining with antibodies against E-selectin, intercellular adhesion molecule, von Willebrand factor, ephrin receptor B4, CD34 and a carbohydrate epitope specific to HEVs (MECA-79). Immune cell distribution and characterization was determined by antibodies recognizing CD45 and CD3 by IF staining- and flow cytometry-based analyses. Antibodies against c-c motif chemokine ligand 21 (CCL21) and lymphotoxin-beta were used in IF staining and Western blot analyses of decidual tissues.
    MAIN RESULTS AND THE ROLE OF CHANCE: Functional HEVs are found in high numbers in the secretory endometrium and decP but decline in numbers upon placentation in decB (P ≤ 0.001). Decidua parietalis tissues contain higher levels of the HEV-maintaining factor lymphotoxin beta and decP-associated HEVs also express CCL21 (P ≤ 0.05), a potent T-cell chemoattractant. Moreover, there is a positive correlation between the numbers of decidual HEVs and the abundance of CD3+ cells in decidual tissue sections (P ≤ 0.001). In-depth analysis of a RPL tissue collection revealed a decreased decB (P ≤ 0.01) and decP (P ≤ 0.01) HEV density as well as reduced numbers of T cells in decB (P ≤ 0.05) and decP (P ≤ .001) sections when compared with age-matched healthy control samples. Using receiver-operating characteristics analyses, we found significant predictive values for the ratios of CD3/CD45 (P < 0.001) and HEVs/total vessels (P < 0.001) for the occurrence of RPL.
    LIMITATIONS, REASONS FOR CAUTION: Analyses were performed in first trimester decidual tissues from elective terminations of pregnancy or non-pregnant endometrium samples from patients diagnosed with non-endometrial pathologies including cervical polyps, ovarian cysts and myomas. First trimester decidual tissues may include pregnancies which potentially would have developed placental disorders later in gestation. In addition, our cohort of non-pregnant endometrium may not reflect the endometrial vascular phenotype of healthy women. Finally, determination of immune cell distributions in the patient cohorts studied may be influenced by the different modes of tissue derivation. Pregnancy terminations were performed by surgical aspiration, endometrial tissues were obtained by biopsies and RPL tissues were collected after spontaneous loss of pregnancy.
    WIDER IMPLICATIONS OF THE FINDINGS: In this study, we propose an inherent mechanism by which the endometrium and in particular the decidua control T-cell recruitment. By demonstrating reduced HEV densities and numbers of T cells in decB and decP tissues of RPL samples we further support previous findings reporting an altered vascular phenotype in early pregnancy loss. Altogether, the findings provide important information to further decipher the etiologies of unexplained RPL.
    STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Austrian Science Fund (P31470 B30 to M.K.) and by the Austrian National Bank (17613ONB to J.P.). There are no competing interests to declare.
    TRIAL REGISTRATION NUMBER: N/A.
    Keywords:  T cells; decidua; high endothelial venules; pregnancy; recurrent pregnancy loss
    DOI:  https://doi.org/10.1093/humrep/deaa234
  3. Front Immunol. 2020 ;11 1785
    Swieboda D, Littauer EQ, Beaver JT, Mills LK, Bricker KM, Esser ES, Antao OQ, Williams DT, Skountzou I.
      While the majority of influenza-infected individuals show no or mild symptomatology, pregnant women are at higher risk of complications and infection-associated mortality. Although enhanced lung pathology and dysregulated hormones are thought to underlie adverse pregnancy outcomes following influenza infection, how pregnancy confounds long-term maternal anti-influenza immunity remains to be elucidated. Previously, we linked seasonal influenza infection to clinical observations of adverse pregnancy outcomes, enhanced lung and placental histopathology, and reduced control of viral replication in lungs of infected pregnant mothers. Here, we expand on this work and demonstrate that lower infectious doses of the pandemic A/California/07/2009 influenza virus generated adverse gestational outcomes similar to higher doses of seasonal viruses. Mice infected during pregnancy demonstrated lower hemagglutination inhibition and neutralizing antibody titers than non-pregnant animals until 63 days post infection. These differences in humoral immunity suggest that pregnancy impacts antibody maturation mechanisms without alterations to B cell frequency or antibody secretion. This is further supported by transcriptional analysis of plasmablasts, which demonstrate downregulated B cell metabolism and post-translational modification systems only among pregnant animals. In sum, these findings corroborate a link between adverse pregnancy outcomes and severe pathology observed during pandemic influenza infection. Furthermore, our data propose that pregnancy directly confounds humoral responses following influenza infection which resolves post-partem. Additional studies are required to specify the involvement of plasmablast metabolism with early humoral immunity abnormalities to best guide vaccination strategies and improve our understanding of the immunological consequences of pregnancy.
    Keywords:  B cell; cellular immunity; hormones; humoral immunity; immunology; influenza; metabolism; pregnancy
    DOI:  https://doi.org/10.3389/fimmu.2020.01785
  4. Am J Reprod Immunol. 2020 Sep 18. e13348
    Simpson S, Kaislasuo J, Peng G, Aldo P, Paidas M, Guller S, Mor G, Pal L.
      PROBLEM: It is unknown if maternal cytokine production differs between twin and singleton gestations in the implantation phase. A difference in maternal serum cytokine concentrations in twins would imply a dose-response to the invading embryos, as opposed to a general immune reaction.METHOD OF STUDY: A prospective longitudinal cohort of women aged 18-45 at an academic fertility center undergoing in vitro fertilization and embryo transfer (IVF-ET) underwent routine collection of serial serum samples starting 9 days after ET and then approximately every 48 hours thereafter. Cryopreserved aliquots of these samples were assayed for interleukin-10 (IL-10), tumor necrosis factor alpha (TNFα) and C-X-C motif chemokine ligand 10 (CXCL10) using the SimplePlex immunoassay platform. Pregnancies were followed until delivery. Serial measures of serum concentrations of IL-10, CXCL10 and TNFα in singleton or di-di twin pregnancies from 9-15 days after IVF-ET were compared.
    RESULTS: Maternal serum levels of CXCL10 are significantly lower in women with di-di twin pregnancies in early implantation compared to those with singleton gestation (day 9-11, p=0.02). Serum levels of TNFα and IL-10 were comparable at all studied time points (p>0.05).
    CONCLUSION: Maternal serum levels of CXCL10 are significantly lower in the earliest implantation phase in di-di twins compared to singleton conceptions. Given the known anti-angiogenic role of CXCL10, we hypothesize that lower CXCL10 levels in twin implantations allows an environment that is conducive for the greater vascularization required for the establishment of dual placentation in di-di twins.
    Keywords:  CXCL10; SimplePlex; cytokines; implantation; twins
    DOI:  https://doi.org/10.1111/aji.13348
  5. J Clin Endocrinol Metab. 2020 Sep 16. pii: dgaa660. [Epub ahead of print]
    Nogues P, Dos Santos E, Couturier-Tarrade A, Berveiller P, Arnould L, Lamy E, Grassin-Delyle S, Vialard F, Dieudonne MN.
      CONTEXT: Maternal obesity has a significant impact on placental development. However, this impact on placenta's structure and function (i.e. nutrient transport, and hormone and cytokine production) is a controversial subject.OBJECTIVE: We hypothesized that maternal obesity is associated with morphologic, secretory and nutrient-related changes and elevated levels of inflammation in the placenta.
    DESIGN: We collected samples of placental tissue from two well-defined groups of pregnant women from 2017 to 2019. We compared the two groups regarding the placental cytokine and hormone secretion, immune cell content, morphology, and placental nutrient transporter expressions.
    SETTING: Placenta were collected after caesarean section performed by experienced clinicians at CHI of Poissy-Saint-Germain-en-Laye.
    PATIENTS: The main inclusion criterion was an age between 27 and 37, no complications of pregnancy and a first-trimester BMI of 18-25 kg/m² for the non-obese (control) group and 30-40 kg/m² for the obese group.
    RESULTS: In contrast to our starting hypothesis, we observed that maternal obesity was associated with (i) lower placental IL-6 expression and macrophage/leukocyte infiltration, (ii) lower placental expression of GLUT1 and SNAT1-2, (iii) a lower placental vessel density, and (iv) lower levels of placental leptin and hCG production.
    CONCLUSION: These results suggest that placenta is a plastic organ and could optimize fetal growth. A better understanding of placental adaptation is required because these changes may partly determine the fetal outcome in cases of maternal obesity.
    Keywords:  inflammatory status; maternal obesity; morphology; placental nutrient transport
    DOI:  https://doi.org/10.1210/clinem/dgaa660